Process gas filtration

ABSTRACT

The present invention relates to a spray drying system provided with a gas filtering system, which system is intended for use in the pharmaceutical industry for aseptic production of sterile pharmaceutical products or in other industries e.g. production of food, where an intake of sterile air for the drying process is necessary. The spray drying system for providing a particulate material comprises a spray drying chamber ( 3 ), after treatment equipment ( 4, 5 ) placed downstream of the spray drying chamber and a process gas heater ( 2 ) placed upstream in relation to the spray drying chamber ( 3 ), wherein an inlet filter ( 1 ) capable of removing microorganisms at a temperature below 140° C., is placed upstream of the process gas heater ( 2 ) and that the process gas heater ( 2 ) is a non-flaking heater.

The present invention relates to a spray drying system provided with agas filtering system, which system is intended for use in thepharmaceutical industry for aseptic production of sterile pharmaceuticalproducts or in other industries e.g. production of food, where an intakeof sterile air for the drying process is necessary.

PRIOR ART

A spray drying system for a pharmaceutical process is normally of a sizewhere the expected use of air would be around 25-5000 kg/hour. It iswell known to provide such a spray drying system with a heat resistantfilter placed between the spray drying chamber and the process gasheater; such a filter should be able to resist the hot process gas andexcessive heating both through sterilization and subsequent processes.As these prior art spray drying systems use a filter located after theprocess gas heater the process is named “hot gas filtration”.

The most commonly used heater for the process gas is an electric processgas heater, this heater has a complex geometry and is thereforedifficult to clean but the electric heater is inexpensive and thereforea popular heating solution. A further problem is that an electric heatercan release flakes of metal scale into the process gas because theheating element experiences high temperatures, when using an electricprocess gas heater, the filter positioned downstream in relation to theelectric heater aims at acting as a cleaning barrier both filtering outany potential scale coming from the electric process gas heater andfiltering out microorganisms and dust particles contained in the heatedprocess gas.

Generally, filtering of hot gas is a challenge; an often used filter forhot process gases is a Termikfil 2000 from the company Camfil Farr, Inc.This filter is at present one of the most used filters for hot gasfiltration on the market. The filter media in the Termikfil 2000 filterconsist of a high-temperature, microfine ceramic based media; the filterhas a maximum operating temperature of 350° C. and is certified to anefficiency of 99.99% on particles of 0.3 micron in size.

The following problems are related to the use of such a traditionalfilter for hot gases:

A) The traditional filter is a HEPA (high-efficiency particulate air)grade filter (traps minimum 99.97% of all particulates larger than 0.3microns) and such a filter does not filter out all viruses and bacteriafrom the inlet gas. Further an upstream electric heater does not undernormal process conditions have the residence time and the temperature toprovide sterilization of the gas. If the filter is used at a temperatureof 260° C. or higher this is not a problem because the high temperaturein itself provides sterile conditions but unfortunately spray dryingchambers within the pharmaceutical industry do not normally operate at260° C. Spray drying of pharmaceutical products typically applies aninlet gas temperature between 100-180° C., and this temperature is nothigh enough to keep the system free of micro organisms aftersterilization.

B) It is difficult to find a filter which is guaranteed non-sheddinge.g. the Termikfil 2000 filter manufacturer will not guaranty the filteris non-shedding.

C) The Termikfil 2000 manufacturer does not claim that the filtermaterials are 21 CFR compliant, the filter is made of ceramic fibersthat are held together by a binder.

D) Current available hot gas filter elements are not suitable for inlinesteam sterilization.

E) The filter cannot be re-used once it has been taken out of itshousing without compromising filter integrity.

F) The filter is expensive (about $9000 for a single element).

G) The filter requires a burn-in process to insure that all the binderholding together the fibers in the filter element are stable and notvaporizing. This burn-in process must be performed in place in theaseptic spray drying chamber it services. Smoke is expelled from thefilter during burn in requiring the spray drying chamber processor to becleaned. The burn in and the cleaning of this filter are costly to theuser because it takes away time where the process equipment could bemaking product.

H) HEPA filters (media and seals) cannot withstand the temperatureswithin the “hot filtration” used for depyrogenation. The binder burnsoff the media leaving a residue similar to the mantel of a gas lantern.The expansion and contraction of the metal frame destroys the sealsbetween the filter frame and the structure as well as the media to theframe. Any oils (PAO or DOP) used to challenge filters in zones thatwill be heated will outgas. The hot oil vapor can deposit on coldersurfaces (drying chamber) due to thermophoresis. The aerosol challengerequired to test the filter integrity may become a product contaminant.

It is difficult to heat the whole system adequately during the requiredsterilization process due to heat losses from the outer surfaces of thespray drying system and due to different heat transfer conditions fromthe inner surface to the outer surface in the walls of the spray dryingsystem. One way to solve this problem is to apply an excessiveinsulation to the equipment which equipment comprises both the spraydrying chamber and any after treatment equipment being in contact withthe product. Another way is to supplement the process gas heater withlocal heaters e.g. with electrical heat tracing applied in places withcold bridges in order to insure aseptic conditions. Using hot gas toheat all the inner surfaces of the system which are in contact with themedia to e.g. at least 170° C. for 1 hour requires excessive gas inlettemperatures, possibly temperatures exceeding the manufacturer'srecommendation of the system gaskets. Exceeding a maximum temperaturefor a material specification in the system would not comply with CGMPstandards.

Further the commonly used spray drying chamber sterilization systemshave been difficult to validate by users because it is difficult toachieve the minimum sterilization temperature on ail inner surfaceswithout compromising the integrity of gaskets and filter elements.

SUMMARY OF THE INVENTION

According to the present invention the process gas is first filtered andthen the process gas is heated in a heating device which does notrelease particles. In such a system the spray drying chamber can besupplied with sterile gas from a filtering system that filters allviruses and bacteria from the process gas before the gas passes theheater, this process is therefore named “cold gas filtration”. Theprocess gas will, after having passed through the cold filter, besterile.

The inlet process gas filter has the following characteristics asspecified by its manufacturer.

-   A) 0.003 uM rating (NaCl CNC particle analysis)-   B) PTFE double layer membranes-   C) 100% bacteria, viruses and particles retentive in gases-   D) USP Biological reactivity test in vivo for class VI-121 C    plastics-   E) Meet cleanliness per USP particulates in injectable-   F) Non-fiber releasing-   G) Non-Pyrogenic per USP Bacterial-   H) Endotoxins (<0.25 EU/ml)-   I) Manufactured with FDA-listed Materials per 21 CFR

Pyrogenics, other bacteria and viruses are removed from the filter andthe ductwork by washing with clean water e.g. with WFI water (Water ForInjection—highly purified water) before the steam sterilization process.Afterwards the filter positioned upstream of the heater, the heater andthe ductwork before the heater are sterilized with steam.

Two different processes needing heating are performed in the spraydrying system: a production process and a sterilization process.

Sterilization in dry heat requires that all surfaces in the system beingin contact with the product is heated e.g. to a minimum temperature of170° C. and held for at least one hour.

The sterilization process would normally require that the process gashas to be heated to a temperature around 250° C. in order to maintain aminimum surface temperature in the process equipment of at least 170° C.

Instead of heating the process to such an excessive temperature thesystem according to the invention can be supplied with general surfaceheaters also called blanket heaters covering the drying chamber, outletductwork and the gas/particle separator system which might be in theform of a cyclone. A general surface heater can provide a continuousheating of the outer surfaces of the equipment which on thecorresponding inner surface are in contact with the processed media. Theblanket heaters are manufactured specifically for this use. The heaterscan be made with a multi stranded element that has a serpentine patternacross the blanket. The blanket panel has embedded two RTD's. One RTD(Resistance Temperature Detector) is for heater control and the other isfor temperature monitoring.

The heater element is sandwiched between sheets of high temperaturematerials, i.e. silicone. There are between 5 and 60 panels that willheat each piece of equipment depending on size. The surface heaters willnormally be designed to heat the neighboring inner vessel surfaces tobetween 180-220° C. The surface heaters supplements the process gasheaters in order to reach the high temperatures required duringsterilization and to reduce sterilization cycle time. The heating of theprocess gas is provided by the indirect heater e.g. a cleanable shelland tube heat exchanger using thermal fluid as a heating media or highpressure steam. The heat exchanger could also be a double tube sheetdesign commonly used in sanitary applications. By this process it caneasily be insured that a sterilization temperatures between 180 and 210°C. can be reached, normally 180° C. is the minimum accepted by mostusers.

A non-flaking heater is a heater which does not release particles whenheated; the releasing of particles is normally the result of acombination of the material used for the heating surfaces and hightemperatures. If the surface temperature of the heating surfaces in theheater can be kept below around 400° C., there will normally not beproblems with flaking.

The process gives a fast heat up of the equipment and it is alsopossible to add a cooling circuit to the indirect heater to enable fastequipment cool down thereby shortening the sterilization cycle times.

This heating combination also has the advantage that it will not benecessary to excessively insulate the drying chamber in order for thesterilization process to take place. This heating system thereforeprovides a faster sterilization cycle allowing the user to increase theproduction time and thereby increase the amount of product produced.Further the heating combination also provides a uniform heating of theinner surfaces thereby making it easier to validate the system. That theheating is uniform means that the resulting temperature of the innersurfaces only varies with around 20° C. throughout the system.

A system according to the present invention is a more robuststerilization technique and therefore easier to validate and shortensthe time required to validate the heating cycles.

Using a spray drying chamber with maintenance access through the topmakes it even more appropriate to use surface heaters e.g. in the formof blanket heaters to warm the surfaces of the spray drying systembecause inappropriately positioned flanges such as heavy flanges in thebottom chamber section are not needed for access and can therefore beeliminated. Therefore the lower section of the spray drying chambercomprises continuous walls without elements e.g. in the form of accessflanges reducing the heat transfer at the bottom part of the spraydrying chamber. There is usually no problem in heating the part of thespray drying chamber where the heated gas enters as the temperaturearound the entrance is relatively high, the entering position willnormally be at the top part. Use of elements such as flanges inpositions relatively far away from the entering of the heated gas e.g.at the bottom part of the spray chamber or the cyclone, will normallyresult in the formation of cold spots which require supplemental localheating in order to reach the defined sterilization temperature.

An appropriate filter for the process would be an ULPA filter (Ultra LowPenetration Air) filter. An ULPA filter is defined as a filter that hasa minimum efficiency of 99.999% for particles in the most penetratingparticle size at the specified media velocity. The most penetratingparticle size is defined as that particle diameter for which penetrationthrough the medium is a maximum.

An appropriate filter for the inlet process gas for cold filtrationwould fulfill the following specifications:

-   A) 0.003 uM rating (NaCl CNC particle analysis) particle retention-   B) polytetrafluoroethylene (PTFE) double-layer membranes-   C) 100% bacteria, viruses and particles retentive in gases-   D) Meets USP Biological Reactivity, In Vivo, for Class VI-121° C.    plastics-   E) Meets cleanliness per USP Particulates in Injectables-   F) Non-fiber releasing-   G) Non-Pyrogenic per USP Bacterial Endotoxins (<0.25 EU/ml)-   H) Manufactured with FDA-listed Materials per 21 CFR

The filter should be subjectable to steam sterilization and therefore beable to resist 121° C. for at least 15 min.

DESCRIPTION OF FIGURES

FIG. 1 shows an embodiment of a spray drying system according to theinvention.

FIG. 2 shows the body of a spray drying chamber provided with a surfaceheater.

The system comprises an inlet filter 1 which might be consist of severalfilters, a gas heater 2, a spray drying chamber 3, a cyclone 4 forseparating gas and particles, and an outlet filter 5 separating dustfrom the outlet gas. The outlet filter 5 can be combined withpre-filters 5 a for catching larger particles and increase the lifetimeof the outlet filter 5.

Normally ambient air is used as process gas as this is the leastexpensive solution for providing large amounts of process gas butnitrogen is also an often used process gas. During the productionprocess the process gas enters the system through the inlet 6 and isrouted through the filter 1 and then the process gas enters the heater 2where the gas is heated to between 100 and 180° C., the actualtemperature depends on which media is to be processed. The gas issterile after having passed through the filter 1.

Then the gas enters the spray drying chamber 3 through an airdistributor assuring a flow pattern suitable for drying of the media tobe processed. The media enters the spray drying chamber through a feedline 7 and a pressurized gas e.g. nitrogen or air enters through a line8 and is used as an atomization gas in one or more fluid nozzlesprovided at the top of the spray drying chamber 3. The pressurized gasis sterile and do normally constitute around 3% of amount of processgas. The not shown nozzles enable proper atomization of the liquidproducts into droplets. The sterile media is thus entering the spraydrying chamber through the top section and is dried to a powder in thespray drying chamber. After having been dried, the gas/particlesuspension is transferred to a cyclone 4 via a ductwork 11, and in thecyclone 4 the suspension is separated into respectively a particlefraction and a gas fraction. The gas fraction exits the cyclone througha conduct 9 and is filtered through the filter 5 which might comprise aseries of filters in order to remove the remaining amount of particlesbefore the drying gas is either exhausted or recycled.

Before starting up production the system must be cleaned andsterilized/depyrogenated. The initial system cleaning is done via aseries of cleaning nozzles throughout the drying system wetting allproduct contact surfaces. Alternatively ductwork e.g. between the inletfilter and the spray drying chamber can be cleaned via flushing byrunning the cleaning solutions through this section. A typical cleaningcycle would start with a potable water flush and then with a series ofchemicals and detergents finishing off with a potable water flush and apurified water rinse. Rinsing endpoints maybe determined by analyticalmeasurement like conductivity.

Sterilization and depyrogenation takes place in three phases:

-   A) The section between the inlet filter system and the spray drying    chamber is washed with caustic and/or purified water, then steam    sterilized.-   B) The balance of the dry gas system will be dry heat sterilized and    depyrogenated by heating all surfaces to between 170 and 210° C. and    holding until the depyrogenation is complete. This process may    require between 4 and 8 hours. The system is heated via a    combination of heated gas from the process heater and the    supplemental blanket heaters covering the drying chamber outlet    ductwork and the cyclone. During this process there maybe a by pass    of gas through the lower section of the cyclone heating the cyclone    lower section.-   C) The feed line and atomization gas line. These lines will be    washed with purified water and then steam sterilized. Some dry heat    sterilization maybe take place downstream of the atomization gas    heater.

After sterilization the system is cooled to operating temperature. Thesystem cooling can be assisted with a cooler located in the thermalfluid circuit. During the cooling procedure the process gas heatexchanger can be turned into a cooler, cooling the system. When thesystem is cooled it will again be ready for processing.

FIG. 2 shows a cut-through view of an embodiment of the body of a spraydrying chamber. From this angle it is possible to see the functionallayers of the embodiment. On the outer surface of the inner sheet 12 ofthe spray drying chamber, the blanket heater 13 is positioned. Theblanket heater will normally cover all of the surfaces in contact withprocess gas on the spray drying chamber 3, outlet duct 11 and cyclone 4.A layer of insulating material 14 is placed on the outer side of theblanket heater 13. In order to provide the spray drying chamber 3 with acleanable outer surface, the insulating material is covered by a hardplain material e.g. a layer of fully welded stainless steel.

1. Apparatus for providing a particulate material for use in thepharmaceutical or food industry, wherein the apparatus comprises a spraydrying chamber, after treatment equipment placed downstream of the spraydrying chamber, and a process gas heater placed upstream in relation tothe spray drying chamber, and wherein a sterile inlet filter configuredto remove microorganisms at a temperature below 140° C. is placedupstream of the process gas heater, and wherein the process gas heateris a non-flaking heater.
 2. Apparatus according to claim 1, wherein theinlet filter can resist steam sterilization at a temperature of at least121° C. for a duration of minimum 15 min.
 3. Apparatus according toclaim 1, wherein the inlet filter is of the dry type filter in a rigidframe having a minimum particle collection efficiency of 99.999% forparticles 0.1 to 0.2 μm when tested in accordance with Methods ofIEST-RP-CC-007.
 4. Apparatus according to claim 1, wherein the aftertreatment equipment comprises a gas/particle separator.
 5. Apparatusaccording to claim 4, wherein the gas/particle separator is one of acyclone or a textile filter or a combination of a cyclone and a textilefilter.
 6. Apparatus according to claim 5, wherein the gas/particleseparator is followed by a dust filter.
 7. Apparatus according to claim1 and comprising a surface heater.
 8. Apparatus according to claim 7,wherein the surface heater comprises a blanket heater.
 9. Apparatusaccording to claim 8, wherein the blanket heater consists of one or moreindividually controlled heaters which together cover at least 30% of theouter surfaces of the apparatus having inner surface contact with theprocess gas.
 10. Apparatus according to claim 1, wherein the spraydrying chamber has a top part and a maintenance opening in the top part.11. Process for cleaning and sterilization of the apparatus according toclaim 1, wherein the process comprises the following steps: a) theapparatus is washed e.g. with clean water (WFI water), b) the filter andheater are sterilized with steam, c) dry gas at a minimum temperature ispassed through the apparatus for a minimum time determined bysterilization demands.
 12. Process according to claim 11, wherein asupplemental surface heater is activated during step c).
 13. Processaccording to claim 11, wherein the surface heater has the form of ablanket heater placed in contact with the outer surface of the productcontact surfaces of the apparatus.